This is a 371 of PCT/EP99/10369 filed Dec. 24, 1999.
The invention relates to the use of pyrimidine derivatives for the prophylaxis and therapy of cerebral ischemia.
DE 1936769.7 describes 3-substituted 3,4,5,6,7,8-hexahydro-pyrido [4xe2x80x2,3xe2x80x2:4,5] thieno [2,3-d] pyrimidine derivatives of the formula I 
where
R1 is hydrogen, a C1-C4-alkyl group, an acetyl or benzoyl group, a phenylalkyl C1-C4 radical, with the aromatic moiety optionally being substituted by halogen, or C1-C4-alkyl, trifluoromethyl, hydroxyl, C1-C4-alkoxy, amino, cyano or nitro groups, a naphthylalkyl C1-C3 radical, a phenylalkanone C2-C3 radical or a phenylcarbamoylalkyl C2 radical, with it being possible for the phenyl group to be substituted by halogen,
R2 is a phenyl, pyridyl, pyrimidinyl or pyrazinyl group which is optionally monosubstituted, disubstituted or trisubstituted by halogen atoms, C1-C4-alkyl or trifluoromethyl, trifluoromethoxy, hydroxyl, C1-C4-alkoxy, amino, monomethylamino, dimethylamino, cyano or nitro groups and which can optionally be fused to a benzene nucleus which can optionally be monosubstituted or disubstituted by halogen atoms, C1-C4-alkyl or hydroxyl, trifluoromethyl, C1-C4-alkoxy, amino, cyano or nitro groups and can optionally contain 1 nitrogen atom, or to a 5- or 6-membered ring which can contain 1-2 oxygen atoms, or can be optionally substituted by a phenyl-C1-C2-alkyl- or alkoxy group, with it being possible for the phenyl radical to be substituted by halogen, or a methyl, trifluoromethyl or methoxy group,
A is NH or oxygen,
B is hydrogen or methyl,
C is hydrogen, methyl or hydroxyl,
X is nitrogen,
Y is CH2, CH2xe2x80x94CH2, CH2xe2x80x94CH2xe2x80x94CH2 or CH2xe2x80x94CH,
Z is nitrogen, carbon or CH, with it also being possible for the bond between Y and Z to be a double bond,
and n is the number 2, 3 or 4.
These compounds of the formula I can be prepared by reacting a compound of the formula II 
in which R1 has the abovementioned meaning, R3 is a cyano group or a C1-3-alkyl-carboxylic ester group, R4 is C1-3-alkyl and C is hydrogen, methyl or hydroxyl, with a primary amine of the formula III 
where R2 and B have the abovementioned meanings, and, where appropriate, converting the resulting compound into the acid addition salt of a physiologically tolerated acid.
The reaction expediently takes place in an inert organic solvent, in particular a lower alcohol, e.g. methanol or ethanol, or a cyclic, saturated ether, in particular tetrahydrofuran or dioxane, or without any solvent.
As a rule, the reaction takes place at from 20 to 190xc2x0 C., in particular from 60 to 90xc2x0 C., and has generally finished within from 1 to 10 hours.
Or, a compound of the formula II 
where R1 has the abovementioned meanings, R3 is a cyano group or a C1-3-alkyl-carboxylic ester group, R4 is C1-3-alkyl and C is hydrogen, methyl or hydroxy, is reacted with a primary amine of the formula IV 
where B has the abovementioned meanings, in an inert solvent, preferably alcohols, such as ethanol, at from 60 to 120xc2x0 C., to give the cyclization product V (D=OH) 
which is then converted with a halogenating agent, such as thionyl chloride or hydrobromic acid, in an organic solvent such as a halogenohydrocarbon, or without any solvent, at from room temperature to 100xc2x0 C., into the corresponding halogen derivative V (D=Cl, Br). Finally, the halogen derivative of the formula V (D=Cl, Br) is reacted with an amine of the formula VI 
where X, Y, Z and R2 have the abovementioned meanings, to give the novel end product of the formula I. This reaction proceeds most efficiently in an inert organic solvent, preferably toluene or xylene, in the presence of a base, such as potassium carbonate or potassium hydroxide, and at from 60 to 150xc2x0 C.
The novel compounds of the formula I can be purified either by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or by means of column chromatography.
The free 3-substituted pyrido[4xe2x80x2,3xe2x80x2:4, 5]thieno[2,3-d]-pyrimidine derivatives of the formula I can be converted, in the customary manner, into the acid addition salts of a solution using the stoichiometric quantity of the corresponding acid. Examples of pharmaceutically tolerated acids are hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfuric acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.